ORIGINAL ARTICLE

Coagulopathy Disproportionately Predisposes to LobarIntracerebral Hemorrhage

Matthew B. Maas • Neil F. Rosenberg •

Adam R. Kosteva • Shyam Prabhakaran •

Andrew M. Naidech

Published online: 9 January 2013

� Springer Science+Business Media New York 2013

Abstract

Background Anticoagulation increases the risk of intra-

cerebral hemorrhage (ICH), yet whether different

underlying disease processes are equally affected is

unknown. We tested the hypothesis that coagulopathy,

measured by admission international normalized ratio

(INR), disproportionately increases the risk for lobar

hemorrhages.

Methods Patients with primary ICH were enrolled into a

registry between December 2006 and February 2012 with

prospective data acquisition and systematic follow up.

Logistic regression was used to test whether lobar versus

deep ICH location was independently associated with INR,

and then whether INR had an influence on mortality.

Spearman’s correlation coefficient was used to test for an

association between INR and hematoma volume separately

in the lobar and deep ICH groups.

Results 221 patients were studied. Patients with lobar

ICH were older (71 vs. 62 years old, p < 0.001) and more

likely to have prior ICH (10 vs. 0 %, p < 0.001). INR

>1.4 was observed on admission more frequently in lobar

versus deep ICH (19 vs. 8 %, p = 0.02). Lobar ICH

location was independently associated with INR >1.4

(OR: 2.51, 95 % CI: 1.03–6.14, p = 0.043). ICH volume

correlated with INR in lobar ICH (p = 0.009), but not deep

ICH (p = 0.8). Death at 1 month was independently

associated with INR >1.4 (OR: 7.6, 95 % CI: 2.4–24.1,

p = 0.001) after correction for the ICH Score.

Conclusions Abnormal coagulation occurs dispropor-

tionally in lobar versus deep ICH, and is associated with

larger ICH volumes and higher mortality. These findings

suggest a unique risk interaction between coagulopathy

and underlying brain pathology due to cerebral amyloid

angiopathy.

Keywords Anticoagulation � Coagulopathy �Intracerebral hemorrhage

Background

Warfarin use increases the incidence and severity of

intracerebral hemorrhage (ICH) [1, 2]. Anticoagulation is

proposed to magnify underlying processes that lead to ICH

such as hypertension and cerebral amyloid angiopathy

(CAA), which predominantly lead to deep and lobar

hemorrhages, respectively [3]. Given the increasing

incidence of anticoagulant associated ICH, a clearer

understanding of the differential effect of anticoagulation

on types of ICH is needed [1].

In this study we tested the hypothesis that abnormal

coagulation, measured by admission prothrombin time/

international normalized ratio (INR), is disproportionately

associated with lobar versus deep hemorrhages.

Methods

Patients presenting to Northwestern Memorial Hospital

with ICH between December 2006 and February 2012 were

prospectively enrolled in an observational registry. All

cases were diagnosed by a board-certified vascular

neurologist or neurointensivist utilizing CT and/or MR

M. B. Maas (&) � N. F. Rosenberg � A. R. Kosteva �S. Prabhakaran � A. M. Naidech

Department of Neurology, Northwestern University,

710 N Lake Shore Drive, 11th Floor, Chicago, IL 60611, USA

e-mail: mbmaas@northwestern.edu

123

Neurocrit Care (2013) 18:166–169

DOI 10.1007/s12028-012-9814-x

imaging. Patients with ICH attributed to trauma, hemor-

rhagic conversion of ischemic stroke, structural lesions, or

vascular malformations were excluded. Demographic

information, clinical data, laboratory results, and follow-up

assessments were prospectively recorded. Hemorrhage

location (lobar, lentiform nucleus, caudate, thalamus,

brainstem, or cerebellum) and the likely etiology of ICH

were adjudicated during the index admission by a board-

certified vascular neurologist or neurointensivist utilizing

all available clinical and imaging data. All patients were

admitted to the neuro-intensive care unit with a standard

order set in the electronic order entry system.

Basic data, including demographic information, medical

history, medication history, standardized clinical instru-

ments [Glasgow coma scale (GCS), National Institutes of

Health Stroke Scale (NIHSS), pre-morbid modified Rankin

scale (mRS)], pretreatment vital signs, and imaging data

were prospectively recorded. Medication reconciliation for

anticoagulant medication was performed by the ICU

pharmacist on admission. Data on medical management,

surgical interventions, and medical complications were

recorded contemporaneously during hospitalization. INR

was the first recorded INR measurement after presentation,

at ours or an outside institution. Hematoma volumes were

measured on industry standard DICOM images from both

referring hospitals and ours using Analyze software (Mayo

Clinic, Rochester, MN) with a semiautomated process, a

technique with high reliability that has been used as an

endpoint in other ICH studies. Fisher’s exact test (for 2

groups of categorical variables), v2 test (for C2 groups of

categorical variables), Student’s t test (for normally dis-

tributed data), and the Mann–Whitney U test (for groups of

non-normally distributed data) were used to compare

characteristics of subjects with lobar versus deep hemor-

rhage. Binary logistic regression models were developed

using variables significant (p B 0.10) in the univariate

analysis to evaluate factors independently associated with

lobar versus deep supratentorial hemorrhage. As a sec-

ondary analysis, we evaluated whether INR was an

independent predictor of death at 3 months by adjusting

first for ICH Score, a widely used composite score of ICH

severity validated as a predictor of functional outcomes at

3 months, and separately using each individual component

of the ICH Score as well as for early withdrawal of care [4,

5]. Spearman’s rank correlation coefficient was used to

evaluate for a relationship between INR and initial ICH

volume separately for patients with lobar and deep ICH.

The study was approved by the Institutional Review

Board (IRB). Written informed consent was obtained from

the patient or their legally authorized representative. The

IRB approved a waiver of consent for patients who died

during initial hospitalization, or who were incapacitated

and for whom a legal representative could not be located.

Results

There were 221 patients analyzed, including 98 with lobar

ICH and 123 with deep ICH. Baseline characteristics of the

subjects are shown in Table 1. On univariate analysis,

patients with lobar hemorrhages were older, predominantly

female and white, less likely to have hypertension, and

more likely to have a history of prior ICH. A greater pro-

portion of lobar ICH cases had admission INR >1.4 (19

vs. 8 %, p = 0.02). Four patients in the cohort had evi-

dence of liver dysfunction, only one of whom, a patient

with a deep ICH, had an elevated INR.

Lobar (versus deep) hemorrhage location was associated

with INR >1.4 (OR: 2.51, 95 % CI: 1.03–6.14, p = 0.043)

after adjustment for age, gender, race, hypertension, and

history of prior ICH. A significant relationship was found

between initial ICH volume and INR among patients with

lobar ICH (p = 0.009) but not among patients with deep

ICH (p = 0.8). Death at 3 months was associated with INR

>1.4 (OR: 7.6, 95 % CI: 2.4–24.1, p = 0.001) after

adjusting for ICH Score, or the individual components

of the ICH Score separately as well as early withdrawal

of care (INR >1.4 OR: 6.45, 95 % CI: 1.24–33.5,

p = 0.026).

Discussion

Our data demonstrate that there is a differential impact of

abnormal coagulation on location of ICH, exerting a

greater effect in lobar ICH. Furthermore, abnormal

coagulation was independently associated with larger

hemorrhage volumes and death in lobar regions but not

deep regions, and with death.

Prior research had identified a link between warfarin use

and mortality after ICH [2]. The mechanism of increased

mortality was unclear, given that another prior study found

no association between warfarin and hemorrhage volume

[6]. In contrast to that work, we assessed the impact of

abnormal coagulation separately in lobar and deep ICH and

used initial INR rather than a reported history of warfarin

use. When we substituted warfarin use for INR, we found a

much weaker association.

A recent study reported an association between cere-

bellar ICH and anticoagulation, defined as a report of

heparin or warfarin use [7]. Given our interest in under-

standing underlying pathophysiology, we chose to directly

compare deep versus lobar supratentorial ICH. Warfarin-

related ICH has been correlated with cerebral microbleeds,

yet recent studies show that microbleeds accumulate over

time in both the lobar and deep regions of the brain, with

approximately 40 % incidence in deep territories [8, 9].

Given that anticoagulation does not directly induce arterial

Neurocrit Care (2013) 18:166–169 167

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rupture, coagulopathy probably causes microbleeds to

enlarge and become clinically evident [3]. We speculate

that anticoagulation destabilizes and amplifies spontaneous

microbleeds caused by CAA more than those caused by

hypertension and other vasculopathic processes. Whereas

the walls of arterioles in deep regions develop lipohyali-

nosis thickening in response to chronic hypertension,

histological examination in CAA in lobar regions has

shown arteriolar wall thinning, interposition of amyloid

deposits between smooth muscle cells, dilated perivascular

spaces, and microaneurysms, and thus less potential for

tamponade [10, 11]. An association between higher apoli-

poprotein E e2 allele frequency and warfarin risk has been

reported in patients with lobar hemorrhage [12].

Several methodological strengths of this study are note-

worthy. First, INR was used in place of the recorded history

of warfarin use. The physiologically meaningful variable is

not whether warfarin had been prescribed but the intensity of

coagulopathy at the time of hemorrhage onset. No patient in

this cohort had exposure to a novel oral anticoagulant. We

hypothesize that a similar effect will be seen with those

agents, but further dedicated study will be needed. Although

this study is limited by being a retrospective analysis from a

single center cohort, the cohort is relatively large, data

acquisition was detailed and prospective, and appropriate

adjustment for potential confounders was performed. An

ideal study of anticoagulation-attributable risk on subtype of

ICH subtype would be a large, prospective cohort study.

Such an endeavor, however, would be costly and resource-

intensive.

Although older anticoagulation decision making models

showed uncertain benefit, our data identifies a vulnerable

Table 1 Baseline

characteristics and predictors of

deep versus lobar ICH

ICH intracerebral hemorrhage,

INR international normalized

ratio, IQR interquartile range,

ARU aspirin resistance units

Deep ICH Lobar ICH Univariate

p value

Multivariate

OR, (95 % CI),

p value

Patients (n) 123 98

Age (mean, SD) 62.1 ± 12.8 71.4 ± 13.6 <0.001 1.05 (1.02–1.07),

p < 0.001

Gender (male, %) 68 (55.3 %) 41 (41.8 %) 0.06 0.60 (0.33–1.09),

p = 0.095

White race (n, %) 45 (36.6 %) 52 (53.1 %) 0.02 p = 0.89

Medical history (n, %)

Intracerebral hemorrhage 0 (0.0 %) 10 (10.2 %) <0.001 p = 0.99

Ischemic stroke 17 (13.8 %) 13 (13.3 %) 0.99

Coronary artery disease 18 (14.6 %) 23 (23.5 %) 0.12

Hypertension 98 (79.7 %) 67 (68.4 %) 0.06 0.45 (0.23–0.89),

p = 0.021

Diabetes 24 (19.5 %) 23 (23.5 %) 0.5

Pack-years smoked (median, IQR) 0 (0–0) 0 (0–10) 0.4

Alcohol abuse 15 (12.2 %) 6 (6.1 %) 0.17

Illicit drug use 3 (2.4 %) 0 (0 %) 0.26

Time from onset to admission

[h (median, IQR)]

3.9 (1.0–9.8) 6.5 (2.9–16.9) 0.007

Initial clinical data

ICH Score (median, IQR) 1 (0–2) 2 (0–3) 0.17

GCS (median, IQR) 13 (8–15) 13 (8–14) 0.4

Hematoma volume in ml

(median, IQR)

8.6 (3.5–17.2) 23.4 (9.9–47.5) <0.001

Location

Lobar (n, %) 0 (0.0 %) 98 (100.0 %)

Lentiform nucleus (n, %) 47 (38.2 %) 0 (0 %)

Caudate (n, %) 9 (7.3 %) 0 (0 %)

Thalamus (n, %) 67 (54.5 %) 0 (0 %)

INR >1.4 (%) 10 (8.1 %) 19 (19.4 %) 0.02 2.51 (1.03–6.14),

p = 0.043

ARU <550 52 (42.3 %) 42 (42.9 %) 0.5

168 Neurocrit Care (2013) 18:166–169

123

subpopulation, and MRI-based screening for lobar micro-

bleeds incorporating updated risk assessments may yet

prove useful [13]. In sum, we found that anticoagulation

and an elevated INR were uniquely associated with lobar

hemorrhage, and worse outcome from lobar hemorrhages.

Conflict of interest None.

Source of Funding Departmentally funded.

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